Recent advances in smoking cessation have focused on the use of antidepressants for the treatment of nicotine dependence (i.e., bupropion and nortriptyline). While the efficacy of these treatments has been established in previous studies, we know little about how they work, particularly on symptoms of negative affect, which are both a strong predictor of relapse and a primary target of these drugs. The impact of these and other pharmacological treatments may be enhanced by improving our understanding of the psychobiological and genetic mechanisms associated with the modulation of mood during cessation and the interaction between these mechanisms and treatment. The specific aims of this project are to assess the effects of these drugs on changes in emotional reactivity during cessation, and to determine if these effects are moderated by genotype. We will also determine whether emotional reactivity predicts time to relapse. The startle reflex (eye blink) is an emerging technology for studying the impact of drugs, genetic factors and other psychobiological mechanisms on emotional processing. The startle reflex is an orienting response that follows an unexpected auditory stimulus (startle probe). Negative emotional cues (unpleasant pictures) activate defensive neuroregulatory pathways and increase blink response magnitude (eye muscle EMG), while positive cues (pleasant pictures) inhibit the response, activating appetitive or approach behavior, in defensive activation, while positive cues inhibit the response (appetitive activation). Our previous studies suggest that this response is modulated before and after quitting by the DRD2 genotype. In this study, up to 354 smokers will be randomly assigned to receive bupropion, nortriptyline or placebo. Participants will complete a startle assessment at baseline (pre-quit) and at 2, 5 and 28 days post-quit, consisting of the presentation of an acoustic stimulus (startle probe), immediately preceded by positive, negative or neutral emotional cues or smoking related stimuli. We hypothesize that the emotional reactivity of all smokers during cessation will be significantly less for those treated with either antidepressant in comparison to placebo. It is also hypothesized that emotional reactivity will be lower for those carrying the DRD2 A1 allele and using bupropion versus A1 smokers using either nortriptyline or placebo. Homozygous A2s are expected to respond similarly to both drugs with higher levels of emotional reactivity being observed for placebo. We will also characterize other potential markers for neurotransmitter function (DRD4, DAT, SERT, NET) in terms of differences in both baseline emotional reactivity, and response to pharmacotherapy vs: the control. We hope to understand more fully how pharmacotherapies for smoking cessation affect emotional reactivity during cessation (nicotine withdrawal) and what role genetics may play in conferring an advantage to one treatment versus another, through this mechanism. Ultimately this knowledge may be applied to the development of more effective smoking cessation treatments, especially in the area of pharmacogenetics.